FI86417C - Process for the preparation of acetyl dicarnitine - Google Patents

Description

8641 7 METHOD OF MANUFACTURE OF ACETYL DICARNITINE

The present invention relates to an intermolecular ester of dicarnitine which has a therapeutic effect.

In particular, the present invention relates to acetyldi-carnitine dichloride having the following general formula:

CH

I 3, CH 0 ^ -CH -CH-CH -COOH CH 2 Cl "3 | 2/1 * I ©

CH 0-C-CH -CH-CH-N-CH

3 II 2 I 2 fcH 3 I

O O-C-CH 3 l 3

The present invention further relates to a process for the preparation of acetylcarnine dichloride.

According to the present invention, the preparation of acetyldicarnitine dichloride of formula I is based essentially on two alternative reactions. First: in said reaction, acetylcarnitine chloride is converted to the corresponding acyl chloride by treatment with thionyl chloride and further esterification with carnitine chloride, in a single step.

According to an alternative reaction, the starting compound is m / m dicarnitine dichloride, intermolecular carnitine: an ester obtained in one step by treatment of carnitine chloride with thionyl chloride and acetylation of E *. further, in a known manner, secondary, free of alcohol. group with acetic anhydride or acetyl chloride, 2 86417 acting as an acylating agent.

The use of thionyl chloride as an acid catalyst and dehydrator is known in the literature.

The transformation of the carboxyl group to the corresponding acyl halide, followed by easier esterification with the alcohol substrate present in the reaction mixture, is a very characteristic and important synthesis that can promote the condensation of two molecules of carnitine and acetylation of the resulting dicarnitine by further addition of acetic anhydride or acetic anhydride.

The reaction may be carried out in a single step, starting with carnitine chloride or acetyl carnitine, without isolating the intermediate compounds thus obtained.

It is an important object of the present invention to find the characteristic conditions of the method according to the present invention. Thus, optimal control of these conditions is very important and accurate. Furthermore, it has been found that prolonged heating or high temperature causes the removal of water from the β-trimethylaminocrotonic acid.

In particular, the compound obtained by the process of the present invention is somewhat unsustainable, and is easily hydrolyzed in an acidic medium so that its separation from the reaction mixture is very accurate. It has been found that isolation is preferably performed immediately and very accurately. On the other hand, methods known in the literature also require special precision.

The preparation of acetyldicarnitine-3,86417 dichloride according to the present invention is carried out starting from a mixture of acetylcarnitine chloride and freshly distilled thionyl chloride, in a molecular ratio of 1: 1.5 ·

The mixture is stirred at room temperature for 0.5-2 hours. The acyl chloride of acetylcarnitine thus obtained, dissolved in methylene chloride, is added with an equivalent amount of carnitine chloride and allowed to stand for 18 to 36 hours at 38 ° to 12 ° C. The crude product thus obtained is separated and purified in a known manner.

Acute toxicity: The acetylcarnitine dichloride of the present invention is a virtually non-toxic compound.

It has been found that when administered orally, the LD50 is greater than 20 g / kg (body weight) in mice and greater than 15 g / kg in rats. When administered intravenously, the LD50 is greater than 0.75 g / kg in mice, greater than 1 g / kg in rats, and greater than 2.5 g / kg in dogs.

Pharmacodynamics Following oral administration of acetyldicarnitine dichloride • · 'to mice and elderly rats at a dose of 100 mg / kg (body weight): increased curiosity and responsiveness and improved coordination of movements were observed.

Based on pharmacological experiments performed to determine the pharmacokinetic properties of the product of the present invention and to study its metabolism, it has been found that acetyldicarnitine chloride is cleaved in the body into L-acetylcarnitin and L-carnitine.

> 1 8641 7

Thus, in addition to the pharmacological properties of L-carnitine, which as is known to activate protein metabolism and stimulate digestive secretion, having an anabolic and anorexic action, the compound of the present invention has some new and unexpected properties.

In particular, the compound of the present invention is particularly active in the treatment of primary or secondary (circulatory diseases), age-related and prenatal brain atrophy, as well as changes in memory and attention in the elderly.

The compound of the present invention is also active in the treatment of cardiac diseases, such as acute and chronic local myocardial anemia, myocardial infarction with both latent and overt heart failure and arrhythmias.

L-acetyldicarnitine also has a cardioprotective effect against cardiac damage caused by the use of antitumor anthracyclines.

Furthermore, due to the most favorable pharmacokinetics, the product has a higher bioavailability, resulting in a better effect compared to other drugs available.

The present invention further encompasses pharmaceutical compositions comprising acetyldicornic dichloride.

Pharmaceutical compositions for oral or parenteral administration are active therapeutic agents for the treatment of primary or secondary, age-related or prenatal symptoms of cerebral atrophy, for the treatment of memory and attention deficit disorders in elderly patients, and for vascular diseases. The pharmaceutical compositions comprise a therapeutically effective amount of acetyldicarnitine dichloride and a pharmaceutically acceptable carrier and / or diluent for oral or intramuscular administration.

The proposed amount of acetyldicarnitine dichloride for human patients is between 0.5 and 2.0 g per dose.

The following examples, which are not intended to limit the invention, illustrate it.

EXAMPLE 1 Preparation of L-acetyl cardiol chloride

According to the method described in the literature (Ziegler et al. J. Org. Chem., 1967, p. 3989), 50 ml of acetic acid -1- was added with 8 g of acetyl chloride and stirred for 3 hours. for one hour at 80 ° C. After the addition of 9.9 g of carnitine, the reaction mixture was allowed to stir for 1 hour at 80 ° C. Distillation in vacuo gave; a very thick solution, to which was then added 40 ml of boiling; isopropanol.

The reaction mixture was filtered to remove unreacted carnitine:! and the title product was slowly precipitated by the addition of 50 ml of acetone. A white crystalline solid was obtained. (yield 98%); mp. 180 ° -182 ° C.

0.15 moles of freshly distilled thionyl chloride in acetyldicarnitine dlchlordl was added to 0.1 6 86417 moles of L-acetylcarnitine chloride.

The mixture was stirred for 1 hour at room temperature.

After excess thionyl chloride was removed by distillation under reduced pressure, the corresponding acyl chloride was obtained as a white, fluffy substance which can be easily hydrolyzed in air.

The acyl chloride thus obtained was dissolved in 30 ml of anhydrous methylene chloride, and then 0.105 mol of L-carnityl chloride was added thereto. The resulting mixture was stirred for 24 hours at 40 ° C. The reaction was monitored by thin layer chromatography until L-acetylcarnitine acyl chloride completely disappeared.

After removal of the solvent by evaporation under reduced pressure, the crude product was washed several times with small amounts of methylene chloride.

The white, fluffy, highly hygroscopic compound thus obtained was dissolved in a minimum amount of isopropanol (about 150 ml), and then filtered to remove unreacted carnitine and acetylcarnitine.

Addition of acetone (300 mL) precipitated the product from the filtrate as a white, highly hygroscopic solid, which was washed several times with small amounts of acetonitrile (ca. 20 mL) to remove any small amounts of ester.

The title compound was obtained (yield 90%): IR (DMSO) λmax 1740, 1715 cm-1 IR (KBr) λmax 3550, 2995, 2950, 2900, 1730 cm-1 MS (field desorption) 347, 305, 287, 204, 162 m / e δ 86417 1 H-NMR (200 MHz, DMSO-d 6, 22 ° C) 2.02 (s, 3H, COCH 3) 2.7-2.8 (m, 1H, CH-CH 2 -COO-CH-CH 2 -). COOH) OCOCH 3 3.20 (s, 18H, 2 x N + (CH 3) 3 (3.8- ^, 1 (m, UH, N + -CH 2 -CH-CH 2 -COOCH-CH 2 -N + OCOCH 3 OCOCH 3 5, m , 2H, -CH-CH2-COO-CH-CH2COOH) EXAMPLE 2

Acetylcarbonyl Dichloride 19.7 g (0.1 mol) of carnitine chloride and 35.7 g (0.3 mol) of thionyl chloride were stirred in a flask for about 8 hours at 30 ° C.

Excess thionyl chloride was removed under reduced pressure. After 10 ml of water was added, the reaction mixture was evaporated to dryness.

The crude product was taken up in isopropyl alcohol, filtered and after removal of unreacted carnitine and N-trimethylamino-crotonic acid, if present, the filtrate was allowed to crystallize.

The precipitate thus obtained was then dissolved in 10.2 g (0.1 mol) of acetic anhydride, and the solution was stirred for about 12 hours at 40 ° C.

‘..1 Excess acetic anhydride and acetic acid were removed by distillation under reduced pressure with a water bath (40 ° C).

8 86417

The viscous residue was dissolved in hot isopropyl alcohol, the title product was separated from the reaction mixture in a known manner, in the form of a hygroscopic white solid.

EXAMPLE 3

Preparation of an injectable pharmaceutical composition

The preparation is carried out according to conventional methods, which are known to those skilled in the art of research.

The preferred composition of the injectable form is as follows: acetyldicarnitine dichloride 500 mg glycine 750 mg distilled water 5 ml EXAMPLE

Preparation of an oral pharmaceutical composition

The preparation is carried out according to conventional methods, which are known to those skilled in the art of research.

The preferred composition for oral administration is as follows (bottle size about 15 ml): acetyldicarnitine dichloride 1 g sorbitol 70% aqueous solution 5 g methyl p-hydroxybenzoate 0.010 g apricot essence 0.015 g orange essence 0.025 g distilled water is made up to 10 ml.

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Claims (3)

9 86417 1. An analogous method for the preparation of acetyldicarnitine dichloride of the following general formula which is therapeutically effective in the treatment of age-related and pre-age brain atrophy syndrome, in the treatment of heart disease, and in protein metabolism and stimulates CH I 3 • CH θί-CH -CH-CH -COOH CH is "3 I 2/1 2 Ift3 2 Cl I; CH OC-CH -CH-CH -N-CH 3. ii 2 I 2 3 O OC- CH 3 l 3 characterized in that a mixture of acetylcarnitine chloride and freshly distilled thionyl chloride with a molecular ratio of 1: 1.5 is allowed to stir for 0.5-2 hours at room temperature, and when the excess thionyl chloride is removed, the resulting acyl chloride is dissolved in methylene chloride containing an equivalent amount of carnitine chloride is added and the resulting mixture is kept at 38e-42 ° C for 18-36 hours to give a crude reaction the product which is dissolved in hot isopropyl alcohol and pure acetyldicarnitine is obtained by crystallization. 10 8 0 41 7 1. Analogs of the invention for the preparation of acetyldicarnitine dichlorides with all of the following formulations, which are particularly active in the treatment of senile and pre-senile cerebral involutions -bolisk and anti-anorexic network, Γ CH I 3. CH θΐ-CH -CH-CH -C00H CH _. - 3 | 2; | 2 | 3 2 Cl I CH O-C-CH -CH-CH -N-CH 3. ii 2 I 2 bH 3 O O-C-CH 3 l 3 ..kännetecknat därav, att man omrör en blandning av acetylkarnitin chloride and nyligen distillerad thionylklorid, i. 'molecular weight 1: 1.5, i 0.5 - 2 timmars tid vid rumstempe-'. after treatment with acetyl chloride in the form of acetyl chloride in the form of methylene chloride, i will be treated with the same equivalents of carnitine chloride and the reaction of the reaction with some up to 18 to 36 times in the range of 18 "to 42" - 38 * 42 , the color is isolated and the reaction product is then precipitated with isopropyl alcohol and renal acetyldicarnitine dichloride in the genome by crystallization.